Forebrain Plasticity in Hypertension

高血压前脑可塑性项目是一个新的多学科研究项目，重点研究控制关键前脑中心和心血管系统之间神经体液相互作用的基本生物学过程。该项目的长期目标是阐明这些中心在高血压发病机制和随后的终末器官损伤，特别是脑血管损伤中的作用。PPG的中心主题集中在脑室周围器官之一的皮质下器官（SFO）和下丘脑室旁核（PVN） （SFO的主要输出途径）在交感神经过度活动和激素释放中血压升高的作用。中心假设是，在缓慢发展的高血压中，SFO-PVN轴存在适应性改变（神经可塑性），使其变得不适应，并为神经体液失调驱动高血压和脑血管功能障碍奠定了基础。每个项目都使用低剂量血管紧张素II （Angll）全身输注产生的高血压临床相关小鼠模型来解决中心假设的特定方面。项目1将研究Angll诱导高血压的SFO下游信号机制，重点关注前列腺素作为必要中介的作用。项目2将研究PVN中关键的结构和功能失调机制，这些机制使高血压发生的神经体液功能障碍成为可能。项目3将侧重于PVN的结构和功能改变，这是绝经期女性高血压易感性增加的原因。项目4将解决SFO-PVN轴在高血压对重要脑血管调节机制的有害影响中的作用，这些机制可确保足够的血流输送到大脑。这些项目由一个行政核心、一个分子生物学-小鼠核心、一个神经解剖学-神经科学核心和一个无线电遥测核心提供支持。该计划的一个主要优势是每个项目结合分子，神经解剖学，神经生理学和心血管综合方法来实现既定目标。这些项目由一个高度互动的知名研究人员小组领导，并以彼此的优势为基础，以便一个项目的科学成果与其他项目中提出的研究相互作用。因此，预计该计划的整体科学成果将大于其单个组成部分的总和。

The Forebrain Plasticity in Hypertension Program is a new multidisciplinary research program focused on the fundamental biological processes governing the neurohumoral interaction between key forebrain centers and the cardiovascular system. The long-term objective of the program is to elucidate the role of these centers in the pathogenesis of hypertension and in the ensuing end-organ damage, particularly cerebrovascular damage. The central theme of the PPG focuses on the role of the subfornical organ (SFO), one of the circumventricular organs, and the hypothalamic paraventricular nucleus (PVN), the main output pathway of the SFO, in the sympathetic overactivity and hormonal release underlying the increase in blood pressure. The central hypothesis is that in slow-developing hypertension there are adaptive modifications (neuroplasticity) in the SFO-PVN axis that turn maladaptive, and set the stage for the neurohumoral dysregulation driving the hypertension and the cerebrovascular dysfunction. Each project addresses a specific facet of the central hypothesis using a clinically relevant mouse model of hypertension produced by systemic infusion of a low dose of angiotensin II (Angll). Project 1 will examine the downstream signaling mechanisms in SFO by which Angll induces the hypertension, focusing on the role of prostanoids as essential intermediaries. Project 2 will examine critical structural and functional maladaptive mechanisms in the PVN, which enable the neurohumoral dysfunction underlying the development of hypertension. Project 3 will focus on the structural and functional modifications in the PVN that are responsible for the increased susceptibility to hypertension in menopausal females. Project 4 will address the role of the SFO-PVN axis in the deleterious effects of hypertension on vital cerebrovascular regulatory mechanisms that assure an adequate blood flow delivery to the brain. The Projects are supported by an Administrative Core, a Molecular Biology-Mouse Core, a Neuroanatomv-lmaaina Core and a Radiotelemetrv Core. A major strength of the program is that each project combines molecular, neuroanatomical, neurophysiological and cardiovascular integrative approaches to achieve the stated goals. The projects are led by a highly interactive group of established investigators and build on each other's strengths so that the scientific output of one project interacts synergistically with the research proposed in other projects. Thus, the collective scientific outcome of the Program is anticipated to be greater than the sum of its individual components. Hypertension affects nearly one third of the general population and is a major cause of the disease burden afflicting men and post-menopausal women. The proposal provides an unprecedented look at the cellular and molecular underpinnings of the neurohumoral dysfunction that leads to hypertension and cerebrovascular dysfunction. The results may provide the rational bases for new treatments for hypertension and its devastating effects on the brain, such as stroke and dementia.